{"gene":"CCDC28A","run_date":"2026-04-28T17:28:52","timeline":{"discoveries":[{"year":2011,"finding":"NUP98-CCDC28A fusion protein acts as an oncogene: retroviral transduction of NUP98-CCDC28A into primary murine bone marrow cells followed by transplantation produced a fully penetrant, transplantable myeloproliferative neoplasm-like myeloid leukemia with selective expansion of granulocyte/macrophage progenitors, demonstrating that the fusion promotes proliferative capacity and self-renewal of myeloid progenitors. Notably, transformation by NUP98-CCDC28A was not associated with deregulation of the Hoxa-Meis1 pathway, indicating an alternative leukemogenic mechanism distinct from many other NUP98 fusions.","method":"Retroviral transduction of primary murine bone marrow cells, in vivo transplantation into sub-lethally irradiated recipients, in silico expression analysis","journal":"Haematologica","confidence":"High","confidence_rationale":"Tier 2 — clean in vivo loss/gain-of-function with defined cellular phenotype and pathway placement, replicated by transplantation","pmids":["22058212"],"is_preprint":false},{"year":2024,"finding":"NPM1::CCDC28A fusion protein localizes predominantly to the cytoplasm (more so than NPM1::MLF1), immortalizes mouse bone marrow cells in vitro, and efficiently induces AML in vivo in a mouse transplantation assay. Mechanistically, NPM1::CCDC28A binds to the HOX gene cluster and causes aberrant upregulation of HOX genes in cooperation with XPO1 (nuclear export factor), similar to NPM1c. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation, and NPM1::CCDC28A cells were also sensitive to menin inhibition.","method":"Subcellular localization imaging, in vitro bone marrow immortalization assay, in vivo mouse transplantation AML model, ChIP or chromatin binding assay for HOX cluster, pharmacological inhibition with selinexor and menin inhibitor","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (localization, in vitro/in vivo functional assay, mechanistic pathway with inhibitor validation)","pmids":["39443736"],"is_preprint":false},{"year":2024,"finding":"CCDC28A is highly expressed in testes and is required for male fertility in mice: Ccdc28a knockout mice show bent sperm heads, acrosomal defects, reduced sperm motility, and decreased in vitro fertilization competence, while axoneme, outer dense fibers, and fibrous sheath remain normal. CCDC28A physically interacts with SPACA1 (sperm acrosome membrane-associated protein 1) and GSK3A (glycogen synthase kinase 3a), proteins whose deficiency in mice produces analogous bent-head and abnormal acrosome phenotypes respectively.","method":"Knockout mouse model, sperm morphology analysis, in vitro fertilization assay, Co-immunoprecipitation/interaction assay for SPACA1 and GSK3A","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 — KO mouse with defined phenotypic readout plus Co-IP identifying binding partners","pmids":["38597936"],"is_preprint":false},{"year":2024,"finding":"CCDC28A is expressed specifically in male germ cells (whereas its paralog CCDC28B is expressed in somatic supporting cells). CCDC28A deficiency in knockout mice results in diminished sperm motility and structural disruption of the head-tail coupling apparatus (HTCA), specifically at the capitulum-basal plate junction, causing bending of the sperm head at the neck region and thickening of the tail midpiece, establishing CCDC28A as essential for HTCA formation and sperm tail morphogenesis.","method":"Knockout mouse model, histological analysis, transmission electron microscopy of sperm ultrastructure","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1-2 — KO mouse with ultrastructural (TEM) phenotypic characterization, independent replication of CCDC28A male infertility phenotype","pmids":["39500989"],"is_preprint":false},{"year":2021,"finding":"NPM1::CCDC28A fusion was detected and characterized in AML samples. Functional studies demonstrated that the NPM1::CCDC28A fusion protein harbors an efficient nuclear export signal (NES) — either newly created or present in the CCDC28A partner — that drives cytoplasmic accumulation of the NPM1 fusion protein, supporting cytoplasmic relocation of NPM1 as critical for leukemogenesis.","method":"RNA sequencing, cytogenetic/FISH screening, immunohistochemistry for NPM1 localization, functional NES analysis","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 — localization functionally linked to leukemogenesis via NES characterization, single study","pmids":["34343258"],"is_preprint":false},{"year":2005,"finding":"A novel chromosomal translocation t(6;11)(q24.1;p15.5) in acute megakaryoblastic leukemia creates a NUP98-C6orf80 (CCDC28A) fusion gene, identified by molecular cytogenetics and RT-PCR, establishing CCDC28A as a fusion partner of NUP98.","method":"FISH, RT-PCR with NUP98 forward and CCDC28A (C6orf80) reverse primers","journal":"Genes, chromosomes & cancer","confidence":"Medium","confidence_rationale":"Tier 3 — identification of fusion by RT-PCR and FISH, no functional characterization in this paper","pmids":["16028218"],"is_preprint":false}],"current_model":"CCDC28A encodes a coiled-coil domain protein that, in somatic cells, functions as an oncogenic fusion partner (with NUP98 or NPM1) driving myeloid leukemia via alternative leukemogenic mechanisms including cytoplasmic NPM1 mislocalization and XPO1-dependent HOX gene upregulation; in male germ cells, CCDC28A is essential for sperm head-tail coupling apparatus (HTCA) integrity, acrosome formation, and sperm motility through interactions with SPACA1 and GSK3A, with loss causing male infertility in mice."},"narrative":{"teleology":[{"year":2005,"claim":"Identification of CCDC28A as a novel NUP98 fusion partner in acute megakaryoblastic leukemia established its potential involvement in leukemogenesis, though no functional role was yet defined.","evidence":"FISH and RT-PCR on patient samples carrying t(6;11)(q24.1;p15.5)","pmids":["16028218"],"confidence":"Medium","gaps":["No functional assay for the fusion protein","Mechanism of transformation unknown","Single patient case"]},{"year":2011,"claim":"Demonstrating that the NUP98-CCDC28A fusion is a bona fide oncogene that transforms myeloid progenitors in vivo resolved whether this translocation is a driver versus passenger event, and revealed it operates through a non-canonical mechanism independent of Hoxa-Meis1.","evidence":"Retroviral transduction of murine bone marrow followed by transplantation into irradiated recipients","pmids":["22058212"],"confidence":"High","gaps":["Alternative leukemogenic pathway downstream of NUP98-CCDC28A not identified","Normal function of CCDC28A protein not addressed"]},{"year":2021,"claim":"Characterization of the NPM1::CCDC28A fusion in AML showed that CCDC28A contributes a functional nuclear export signal, establishing cytoplasmic NPM1 mislocalization as a shared leukemogenic mechanism across NPM1 fusions.","evidence":"RNA sequencing, immunohistochemistry for NPM1 localization, and NES functional analysis in AML patient samples","pmids":["34343258"],"confidence":"Medium","gaps":["Whether the NES derives from a de novo junction sequence or from CCDC28A itself was not fully resolved","Downstream effectors of cytoplasmic NPM1::CCDC28A not characterized"]},{"year":2024,"claim":"Mechanistic dissection of NPM1::CCDC28A revealed it binds HOX gene clusters and drives their XPO1-dependent upregulation, connecting the cytoplasmic mislocalization phenotype to a specific transcriptional oncogenic program and identifying actionable therapeutic vulnerabilities (selinexor, menin inhibition).","evidence":"In vitro immortalization, in vivo transplantation AML model, chromatin binding assay, pharmacological inhibition with selinexor and menin inhibitor","pmids":["39443736"],"confidence":"High","gaps":["Whether the NUP98-CCDC28A fusion shares the HOX-dependent mechanism is unknown","Structural basis of NPM1::CCDC28A–chromatin interaction not determined"]},{"year":2024,"claim":"Knockout mouse studies established the first physiological role for CCDC28A: it is essential for HTCA formation, acrosome biogenesis, and sperm motility, interacting with SPACA1 and GSK3A to maintain the capitulum–basal plate junction.","evidence":"Two independent Ccdc28a knockout mouse models with sperm morphology, TEM ultrastructure, in vitro fertilization, and co-immunoprecipitation","pmids":["38597936","39500989"],"confidence":"High","gaps":["Biochemical function of CCDC28A (enzymatic vs. scaffolding) not defined","How CCDC28A coordinates SPACA1 and GSK3A activities at the HTCA is unknown","Human male infertility caused by CCDC28A mutations not yet reported"]},{"year":null,"claim":"The intrinsic molecular activity of CCDC28A protein — whether it acts as a structural scaffold, signaling adaptor, or has other biochemical function — remains undefined, and no structure or enzymatic activity has been reported.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal/cryo-EM structure available","No enzymatic or catalytic activity tested","Somatic cell function of wild-type CCDC28A is entirely uncharacterized"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,4]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[2,3]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["SPACA1","GSK3A","NUP98","NPM1","XPO1"],"other_free_text":[]},"mechanistic_narrative":"CCDC28A is a coiled-coil domain-containing protein with dual roles: in male germ cells it is essential for sperm head-tail coupling apparatus (HTCA) integrity, acrosome formation, and motility, while in somatic cells it participates in oncogenic fusions driving myeloid leukemia. In the testis, CCDC28A physically interacts with SPACA1 and GSK3A, and its loss in knockout mice causes structural disruption of the capitulum–basal plate junction, bent sperm heads, thickened midpieces, and male infertility [PMID:38597936, PMID:39500989]. CCDC28A is recurrently rearranged as a fusion partner of NUP98 and NPM1 in acute myeloid leukemia; the NPM1::CCDC28A fusion drives cytoplasmic mislocalization of NPM1 via a nuclear export signal, binds HOX gene clusters, and upregulates HOX genes in an XPO1-dependent manner that is sensitive to selinexor and menin inhibition [PMID:39443736, PMID:34343258]. The NUP98-CCDC28A fusion independently transforms myeloid progenitors through a mechanism distinct from the canonical Hoxa-Meis1 pathway [PMID:22058212]."},"prefetch_data":{"uniprot":{"accession":"Q8IWP9","full_name":"Coiled-coil domain-containing protein 28A","aliases":["CCRL1AP"],"length_aa":274,"mass_kda":30.4,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q8IWP9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CCDC28A","classification":"Not Classified","n_dependent_lines":13,"n_total_lines":382,"dependency_fraction":0.034031413612565446},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CCDC28A","total_profiled":1310},"omim":[{"mim_id":"615353","title":"COILED-COIL DOMAIN-CONTAINING PROTEIN 28A; CCDC28A","url":"https://www.omim.org/entry/615353"},{"mim_id":"601021","title":"NUCLEOPORIN, 98-KD; NUP98","url":"https://www.omim.org/entry/601021"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CCDC28A"},"hgnc":{"alias_symbol":["CCRL1AP","DKFZp586D0623","LTAP2A"],"prev_symbol":["C6orf80"]},"alphafold":{"accession":"Q8IWP9","domains":[{"cath_id":"1.10.287","chopping":"199-267","consensus_level":"medium","plddt":79.2791,"start":199,"end":267}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWP9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWP9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IWP9-F1-predicted_aligned_error_v6.png","plddt_mean":61.53},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CCDC28A","jax_strain_url":"https://www.jax.org/strain/search?query=CCDC28A"},"sequence":{"accession":"Q8IWP9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IWP9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IWP9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IWP9"}},"corpus_meta":[{"pmid":"16467868","id":"PMC_16467868","title":"NUP98 rearrangements in hematopoietic malignancies: a study of the Groupe Francophone de Cytogénétique Hématologique.","date":"2006","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/16467868","citation_count":106,"is_preprint":false},{"pmid":"31648321","id":"PMC_31648321","title":"Transcriptome analysis offers a comprehensive illustration of the genetic background of pediatric acute myeloid leukemia.","date":"2019","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/31648321","citation_count":73,"is_preprint":false},{"pmid":"30575821","id":"PMC_30575821","title":"The genetics and clinical characteristics of children morphologically diagnosed as acute promyelocytic leukemia.","date":"2018","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/30575821","citation_count":57,"is_preprint":false},{"pmid":"34343258","id":"PMC_34343258","title":"Novel NPM1 exon 5 mutations and gene fusions leading to aberrant cytoplasmic nucleophosmin in AML.","date":"2021","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/34343258","citation_count":47,"is_preprint":false},{"pmid":"17233820","id":"PMC_17233820","title":"Fusion of NUP98 and the SET binding protein 1 (SETBP1) gene in a paediatric acute T cell lymphoblastic leukaemia with t(11;18)(p15;q12).","date":"2007","source":"British journal of haematology","url":"https://pubmed.ncbi.nlm.nih.gov/17233820","citation_count":43,"is_preprint":false},{"pmid":"16028218","id":"PMC_16028218","title":"Characterization of 6q abnormalities in childhood acute myeloid leukemia and identification of a novel t(6;11)(q24.1;p15.5) resulting in a NUP98-C6orf80 fusion in a case of acute megakaryoblastic leukemia.","date":"2005","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16028218","citation_count":16,"is_preprint":false},{"pmid":"22058212","id":"PMC_22058212","title":"Functional analysis of the NUP98-CCDC28A fusion protein.","date":"2011","source":"Haematologica","url":"https://pubmed.ncbi.nlm.nih.gov/22058212","citation_count":15,"is_preprint":false},{"pmid":"39443736","id":"PMC_39443736","title":"NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation.","date":"2024","source":"Leukemia","url":"https://pubmed.ncbi.nlm.nih.gov/39443736","citation_count":10,"is_preprint":false},{"pmid":"33415070","id":"PMC_33415070","title":"A Protein Microarray-Based Investigation of Cerebrospinal Fluid Reveals Distinct Autoantibody Signature in Low and High-Grade Gliomas.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33415070","citation_count":10,"is_preprint":false},{"pmid":"23698072","id":"PMC_23698072","title":"Identification of multiple complex rearrangements associated with deletions in the 6q23-27 region in Sézary syndrome.","date":"2013","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/23698072","citation_count":10,"is_preprint":false},{"pmid":"38597936","id":"PMC_38597936","title":"CCDC28A deficiency causes sperm head defects, reduced sperm motility and male infertility in mice.","date":"2024","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/38597936","citation_count":5,"is_preprint":false},{"pmid":"37525634","id":"PMC_37525634","title":"Immune Cell Infiltration Analysis Based on Bioinformatics Reveals Novel Biomarkers of Coronary Artery Disease.","date":"2023","source":"Journal of inflammation research","url":"https://pubmed.ncbi.nlm.nih.gov/37525634","citation_count":5,"is_preprint":false},{"pmid":"39500989","id":"PMC_39500989","title":"CCDC28A deficiency causes head-tail coupling defects and immotility in murine spermatozoa.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39500989","citation_count":3,"is_preprint":false},{"pmid":"40140093","id":"PMC_40140093","title":"A new perspective on endometriosis: Integrating eQTL mendelian randomization with transcriptomics and single-cell data analyses.","date":"2025","source":"Functional & integrative genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40140093","citation_count":1,"is_preprint":false},{"pmid":"41120674","id":"PMC_41120674","title":"Concurrent NPM1::CCDC28A and BCR::ABL1 fusions in extramedullary blast crisis of chronic myeloid leukemia: A case report and literature review.","date":"2025","source":"Annals of hematology","url":"https://pubmed.ncbi.nlm.nih.gov/41120674","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9677,"output_tokens":1791,"usd":0.027948},"stage2":{"model":"claude-opus-4-6","input_tokens":5035,"output_tokens":1606,"usd":0.097988},"total_usd":0.125936,"stage1_batch_id":"msgbatch_011kfMfE81o6CTcyhVUqumuW","stage2_batch_id":"msgbatch_01DTputS6WNkH745x1nVSoBo","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2011,\n      \"finding\": \"NUP98-CCDC28A fusion protein acts as an oncogene: retroviral transduction of NUP98-CCDC28A into primary murine bone marrow cells followed by transplantation produced a fully penetrant, transplantable myeloproliferative neoplasm-like myeloid leukemia with selective expansion of granulocyte/macrophage progenitors, demonstrating that the fusion promotes proliferative capacity and self-renewal of myeloid progenitors. Notably, transformation by NUP98-CCDC28A was not associated with deregulation of the Hoxa-Meis1 pathway, indicating an alternative leukemogenic mechanism distinct from many other NUP98 fusions.\",\n      \"method\": \"Retroviral transduction of primary murine bone marrow cells, in vivo transplantation into sub-lethally irradiated recipients, in silico expression analysis\",\n      \"journal\": \"Haematologica\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean in vivo loss/gain-of-function with defined cellular phenotype and pathway placement, replicated by transplantation\",\n      \"pmids\": [\"22058212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NPM1::CCDC28A fusion protein localizes predominantly to the cytoplasm (more so than NPM1::MLF1), immortalizes mouse bone marrow cells in vitro, and efficiently induces AML in vivo in a mouse transplantation assay. Mechanistically, NPM1::CCDC28A binds to the HOX gene cluster and causes aberrant upregulation of HOX genes in cooperation with XPO1 (nuclear export factor), similar to NPM1c. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation, and NPM1::CCDC28A cells were also sensitive to menin inhibition.\",\n      \"method\": \"Subcellular localization imaging, in vitro bone marrow immortalization assay, in vivo mouse transplantation AML model, ChIP or chromatin binding assay for HOX cluster, pharmacological inhibition with selinexor and menin inhibitor\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (localization, in vitro/in vivo functional assay, mechanistic pathway with inhibitor validation)\",\n      \"pmids\": [\"39443736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCDC28A is highly expressed in testes and is required for male fertility in mice: Ccdc28a knockout mice show bent sperm heads, acrosomal defects, reduced sperm motility, and decreased in vitro fertilization competence, while axoneme, outer dense fibers, and fibrous sheath remain normal. CCDC28A physically interacts with SPACA1 (sperm acrosome membrane-associated protein 1) and GSK3A (glycogen synthase kinase 3a), proteins whose deficiency in mice produces analogous bent-head and abnormal acrosome phenotypes respectively.\",\n      \"method\": \"Knockout mouse model, sperm morphology analysis, in vitro fertilization assay, Co-immunoprecipitation/interaction assay for SPACA1 and GSK3A\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mouse with defined phenotypic readout plus Co-IP identifying binding partners\",\n      \"pmids\": [\"38597936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCDC28A is expressed specifically in male germ cells (whereas its paralog CCDC28B is expressed in somatic supporting cells). CCDC28A deficiency in knockout mice results in diminished sperm motility and structural disruption of the head-tail coupling apparatus (HTCA), specifically at the capitulum-basal plate junction, causing bending of the sperm head at the neck region and thickening of the tail midpiece, establishing CCDC28A as essential for HTCA formation and sperm tail morphogenesis.\",\n      \"method\": \"Knockout mouse model, histological analysis, transmission electron microscopy of sperm ultrastructure\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — KO mouse with ultrastructural (TEM) phenotypic characterization, independent replication of CCDC28A male infertility phenotype\",\n      \"pmids\": [\"39500989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"NPM1::CCDC28A fusion was detected and characterized in AML samples. Functional studies demonstrated that the NPM1::CCDC28A fusion protein harbors an efficient nuclear export signal (NES) — either newly created or present in the CCDC28A partner — that drives cytoplasmic accumulation of the NPM1 fusion protein, supporting cytoplasmic relocation of NPM1 as critical for leukemogenesis.\",\n      \"method\": \"RNA sequencing, cytogenetic/FISH screening, immunohistochemistry for NPM1 localization, functional NES analysis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — localization functionally linked to leukemogenesis via NES characterization, single study\",\n      \"pmids\": [\"34343258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"A novel chromosomal translocation t(6;11)(q24.1;p15.5) in acute megakaryoblastic leukemia creates a NUP98-C6orf80 (CCDC28A) fusion gene, identified by molecular cytogenetics and RT-PCR, establishing CCDC28A as a fusion partner of NUP98.\",\n      \"method\": \"FISH, RT-PCR with NUP98 forward and CCDC28A (C6orf80) reverse primers\",\n      \"journal\": \"Genes, chromosomes & cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — identification of fusion by RT-PCR and FISH, no functional characterization in this paper\",\n      \"pmids\": [\"16028218\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CCDC28A encodes a coiled-coil domain protein that, in somatic cells, functions as an oncogenic fusion partner (with NUP98 or NPM1) driving myeloid leukemia via alternative leukemogenic mechanisms including cytoplasmic NPM1 mislocalization and XPO1-dependent HOX gene upregulation; in male germ cells, CCDC28A is essential for sperm head-tail coupling apparatus (HTCA) integrity, acrosome formation, and sperm motility through interactions with SPACA1 and GSK3A, with loss causing male infertility in mice.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"CCDC28A is a coiled-coil domain-containing protein with dual roles: in male germ cells it is essential for sperm head-tail coupling apparatus (HTCA) integrity, acrosome formation, and motility, while in somatic cells it participates in oncogenic fusions driving myeloid leukemia. In the testis, CCDC28A physically interacts with SPACA1 and GSK3A, and its loss in knockout mice causes structural disruption of the capitulum–basal plate junction, bent sperm heads, thickened midpieces, and male infertility [PMID:38597936, PMID:39500989]. CCDC28A is recurrently rearranged as a fusion partner of NUP98 and NPM1 in acute myeloid leukemia; the NPM1::CCDC28A fusion drives cytoplasmic mislocalization of NPM1 via a nuclear export signal, binds HOX gene clusters, and upregulates HOX genes in an XPO1-dependent manner that is sensitive to selinexor and menin inhibition [PMID:39443736, PMID:34343258]. The NUP98-CCDC28A fusion independently transforms myeloid progenitors through a mechanism distinct from the canonical Hoxa-Meis1 pathway [PMID:22058212].\",\n  \"teleology\": [\n    {\n      \"year\": 2005,\n      \"claim\": \"Identification of CCDC28A as a novel NUP98 fusion partner in acute megakaryoblastic leukemia established its potential involvement in leukemogenesis, though no functional role was yet defined.\",\n      \"evidence\": \"FISH and RT-PCR on patient samples carrying t(6;11)(q24.1;p15.5)\",\n      \"pmids\": [\"16028218\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional assay for the fusion protein\", \"Mechanism of transformation unknown\", \"Single patient case\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrating that the NUP98-CCDC28A fusion is a bona fide oncogene that transforms myeloid progenitors in vivo resolved whether this translocation is a driver versus passenger event, and revealed it operates through a non-canonical mechanism independent of Hoxa-Meis1.\",\n      \"evidence\": \"Retroviral transduction of murine bone marrow followed by transplantation into irradiated recipients\",\n      \"pmids\": [\"22058212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Alternative leukemogenic pathway downstream of NUP98-CCDC28A not identified\", \"Normal function of CCDC28A protein not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Characterization of the NPM1::CCDC28A fusion in AML showed that CCDC28A contributes a functional nuclear export signal, establishing cytoplasmic NPM1 mislocalization as a shared leukemogenic mechanism across NPM1 fusions.\",\n      \"evidence\": \"RNA sequencing, immunohistochemistry for NPM1 localization, and NES functional analysis in AML patient samples\",\n      \"pmids\": [\"34343258\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the NES derives from a de novo junction sequence or from CCDC28A itself was not fully resolved\", \"Downstream effectors of cytoplasmic NPM1::CCDC28A not characterized\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Mechanistic dissection of NPM1::CCDC28A revealed it binds HOX gene clusters and drives their XPO1-dependent upregulation, connecting the cytoplasmic mislocalization phenotype to a specific transcriptional oncogenic program and identifying actionable therapeutic vulnerabilities (selinexor, menin inhibition).\",\n      \"evidence\": \"In vitro immortalization, in vivo transplantation AML model, chromatin binding assay, pharmacological inhibition with selinexor and menin inhibitor\",\n      \"pmids\": [\"39443736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the NUP98-CCDC28A fusion shares the HOX-dependent mechanism is unknown\", \"Structural basis of NPM1::CCDC28A–chromatin interaction not determined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Knockout mouse studies established the first physiological role for CCDC28A: it is essential for HTCA formation, acrosome biogenesis, and sperm motility, interacting with SPACA1 and GSK3A to maintain the capitulum–basal plate junction.\",\n      \"evidence\": \"Two independent Ccdc28a knockout mouse models with sperm morphology, TEM ultrastructure, in vitro fertilization, and co-immunoprecipitation\",\n      \"pmids\": [\"38597936\", \"39500989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical function of CCDC28A (enzymatic vs. scaffolding) not defined\", \"How CCDC28A coordinates SPACA1 and GSK3A activities at the HTCA is unknown\", \"Human male infertility caused by CCDC28A mutations not yet reported\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The intrinsic molecular activity of CCDC28A protein — whether it acts as a structural scaffold, signaling adaptor, or has other biochemical function — remains undefined, and no structure or enzymatic activity has been reported.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal/cryo-EM structure available\", \"No enzymatic or catalytic activity tested\", \"Somatic cell function of wild-type CCDC28A is entirely uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SPACA1\", \"GSK3A\", \"NUP98\", \"NPM1\", \"XPO1\"],\n    \"other_free_text\": []\n  }\n}\n```"}